Glaucoma is a devastating condition associated with irreversible degeneration of the optic nerve head, which can lead to blindness. Although the exact mechanisms contributing to the initiation and progression of most glaucomas are unknown, the primary risk factor is increased intraocular pressure (IOP) (Rhee et al., 2009). IOP is presumably elevated from an abnormal increase in resistance to aqueous outflow within the human trabecular meshwork (HTM) and adjacent Schlemm's canal cells (Last et al., 2011; McKee et al., 2011; Rhee et al., 2009). The HTM is a mechanosensitive structure that is subjected to dynamic strain from changes in intraocular pressure as well as from the ciliary muscle and intrinsic contractile elements (Bradley et al., 2001; Tumminia et al., 1998; Wiederholt et al., 2000). It is comprised of extracellular matrix (ECM) which possesses an intrinsic compliance and complex three-dimensional topography that support and interact with the overlying TM cells. Recently, Last et al. demonstrated that the HTM is stiffer with glaucoma and this change may influence the outflow facility of aqueous humor (Last et al., 2011). In vivo, HTM cells are exposed to dynamic, compliant substrates that markedly differ from flat, rigid substrates such as glass or tissue culture polystyrene (TCP) which are typically used to investigate cellular behavior. Substratum stiffness has been shown to profoundly alter HTM cytoskeletal structure and dynamics, cell stiffness, ECM gene and protein expression patterns, cell behaviors, and the cellular response to therapeutic agents (Han et al., 2011; McKee et al., 2011; Schlunck et al., 2008; Thomasy et al., 2012; Wood et al., 2011a).
While substratum elastic modulus has been shown to modulate a variety of HTM cellular behaviors, the intrinsic mechanisms by which HTM cells perceive biomechanical cues and translate these external stimuli to intracellular signals that control cell behavior and gene transcription remain unknown. A recent study by Dupont et al. identified the Yorkie homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif; encoded by WWTR1), as the nuclear relays of mechanical signals exerted by ECM rigidity (Dupont et al., 2011). YAP and/or TAZ are co-activators of transcription and their specific functions are dependent on their spatial localization within the cellular nucleus or cytoplasm (FIG. 1) (Dupont et al., 2011; Zhao et al., 2010a). When localized to the nucleus, YAP and/or TAZ regulates the activity of multiple transcription factors. YAP and TAZ can be phosphorylated by the large tumor suppressor (LATS) 1/2, triggering cytoplasmic retention and loss of transcriptional activity (Zhao et al., 2010a). Once phosphorylated, YAP and TAZ bind with 14-3-3σ and can be targeted for degradation. If there is a decrease in phosphorylation of YAP and/or TAZ, more nuclear localization is possible. In addition, it has been shown that cells cultured on stiffer substrates have increased nuclear localization of YAP and/or TAZ (Dupont et al., 2011).